This invention relates to new anthracycline derivatives, to their production and recovery, and to their therapeutic use.
A number of anthracycline glycosides have been described in prior literature. Among them, daunomycin and adriamycin are particularly being watched with keen interest by those in the field of cancer chemotherapy and have already been applied clinically for human cancers. Preparation of adriamycin by fermentation of Streptomyces peuceticus var. caesius is disclosed in U.S. Pat. No. 3,590,028. Chemical conversion of daunomycin to adriamycin is taught in U.S. Pat. No. 3,803,124. Daunomycin produced by fermentation of S. peuceticus in U.K. Pat. No. 1,003,383 is the same as Rhone-Poulenc's 13057RP (see U.K. Pat. Nos. 985,598, 1,188,262 and 1,241,750 and U.S. Pat. No. 3,616,242) and as danubomycin disclosed in U.S. Pat. No. 3,092,550 and U.K. Pat. No. 901,830. Dihydrodaunomycin is disclosed in U.S. Pat. No. 3,686,163. The anthracyclinones, .epsilon.-pyrromycinone and .epsilon.-isorhodomycinone, were described in U.S. Pat. No. 3,864,480, Keller-Schierlein et al., Antimicrobial Agents and Chemotherapy, page 68 (1970), Chem. Ber. 92:1904(1959), Chem. Ber. 88:1792(1955) and Tetrahedron 19:395(1963). For further illustrative and summary disclosures of anthracycline antibiotics see Index of Antibiotics from Actinomycetes, Volume 2, Hamao Umezawa, Editor-in-Chief, Japan Scientific Societies Press, Tokyo & University Park Press, Baltimore, U.S.A. (1978) as follows:
______________________________________ ANTIBIOTICS PAGE NUMBERS ______________________________________ Aclacinomycin A & B 101-102 Adriamycin 122 Carminomycin I 225 Daunosaminyldaunomycin 285 Galirubin S-D 405-408 Rhodomycin X-Y 879-880 .beta.-Rhodomycins 881-885 .gamma.-Rhodomycins 886-892 Steffimycin 945 ______________________________________
The textbook, Antibiotics, Vol. 1, Mechanism of Action, edited by D. Gottlieb & P. D. Shaw, Springer-Verlag, New York, Inc., N.Y., N.Y. (1967) on pages 190-210 contains a review of A. DiMarco entitled Daunomycin and Related Antibiotics.
This invention relates to new anthracycline derivatives, to processes for their preparation and to the use of such derivatives in inhibiting the growth and nucleic acid biosynthesis of murine leukemic L1210 cells in culture. More particularly it relates to novel anthracycline glycosides designated herein 1-hydroxy-13-dihydrodaunomycin and N-formyl-1-hydroxy-13-dihydrodaunomycin. The anthracycline derivatives are produced by cultivating a daunomycin-producing strain of streptomyces and blocked mutants therefrom with .epsilon.-pyrromycinone and .epsilon.-isorhodomycinone in an aqueous nutrient medium containing assimilable sources of carbon, nitrogen, inorganic salts and other nutrients necessary for the growth of the microorganism under submerged aerobic conditions until a substantial amount of new anthracycline derivatives are produced by said microorganism in said culture medium and recovering 1-hydroxy-13-dihydrodaunomycin and N-formyl-1-hydroxy-13-dihydrodaunomycin from the culture broth. .epsilon.-Pyrromycinone or .epsilon.-isorhodomycinone was added to the growing culture during the logarithmic phase of streptomyces at the concentration of 10-200 .mu.g/ml, and the glycosidation of aglycone is completed by further aerobic cultivation for 18 to 72 hours. 1-Hydroxy-13-dihydrodaunomycin and N-formyl-1-hydroxy-13-dihydrodaunomycin were recovered and separated by extraction of the whole fermentation broth, with or without the separation of mycelium, or by extraction from mycelium followed by separation and isolation of the component glycosides by standard column chromatographic procedures. 1-Hydroxy-13-dihydrodaunomycin and N-formyl-1-hydroxy-13-dihydrodaunomycin showed a marked antitumor activity in leukemic L1210-bearing mice and lower toxicity than daunomycin in mice.
This invention also embraces 1-hydroxy-13-dihydrodaunomycin and N-formyl-1-hydroxy-13-dihydrodaunomycin as crude solid, as purified solids, and as their non-toxic acid addition salts.